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Diabetic nephropathy (DN) is one of the most important diabetic microangiopathies.Epithelial to mesenchymal transition (EMT) plays an important role in DN.The physiological role of microRNA-21 (miR-21) was closely linked to EMT.However, it remained elusive whether Tongxinluo (TXL) ameliorated renal structure and function by regulating miR-21-Induced EMT in DN.This study was to determine the effect of TXL on miR-21-induced renal tubular EMT and to explore the relationship between miR-21 and TGF-β1/smads signals.Real-time RT-PCR, cell transfection and in situ hybridization (ISH) and laser confocal microscopy were used, respectively.Here, we revealed that TXL dose-dependently lowered miR-21 expression in tissue, serum and cell.Over-expression of miR-21 can enhance a-SMA expression and decrease E-cadherin expression by upregulating smad3/p-smad3 expression and downregulating smad7 expression.Interestingly, TXL also increased E-cadherin expression and decreased a-SMA expression by regulating miR-21 expression.More importantly, TXL decreased col-ⅣV, FN, GBM, GA and albumin creatinine ratio (ACR), whereas, increased creatinine clearance ratio (Ccr).The results demonstrated that TXL ameliorated renal structure and function by regulating miR-21-Induced EMT, which was one of the mechanisms to protect DN, and that miR-21 was novel therapeutic target for TXL in diabetic nephropathy.